Uesawa Yoshihiro, Sakagami Hiroshi, Kagaya Hajime, Yamashita Marimo, Takao Koichi, Sugita Yoshiaki
Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Kiyose, Japan
Division of Pharmacology, Meikai University School of Dentistry, Sakado, Japan.
Anticancer Res. 2016 Nov;36(11):5803-5812. doi: 10.21873/anticanres.11164.
Sixteen 3-benzylidenechromanones were subjected to quantitative structure-activity relationship (QSAR) analysis based on their cytotoxicity and tumor-specificity, in order to examine their new biological activities.
Cytotoxicity against two human oral squamous cell carcinoma cell lines, two mesenchymal and two epithelial normal oral cells, was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Tumor-specificity (TS) was evaluated by the ratio of the mean CC (50% cytotoxic concentration) against normal cells to that against tumor cell lines. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method.
3-Benzylidenechromanone derivatives that have a methoxy group at 7-position of the chromanone ring and hydroxyl or methoxy group at 4'-position of benzene ring showed relatively higher TS values, exceeding those of doxorubicin (DXR) and 5-fluorouracil (5-FU). Since these anticancer drugs were highly cytotoxic to normal keratinocytes, QSAR analysis was performed with oral carcinoma and mesenchymal normal cells. Tumor-specificity was well correlated with 3D-MoRSE descriptors (that relate to three dimensional shapes) and Edge adjacency indices (that relate to two dimensional shapes and polarization). Introduction of hydroxyl group at 3'-position of benzene ring significantly elevated the tumor-specificity.
Molecular shape, size and polarization are useful markers for the evaluation of tumor-specificity of 3-benzylidenechromanone derivatives.
基于16种3 - 亚苄基色满酮的细胞毒性和肿瘤特异性进行定量构效关系（QSAR）分析，以研究其新的生物学活性。
采用3 -（4,5 - 二甲基噻唑 - 2 - 基）- 2,5 - 二苯基四氮唑溴盐法测定对两种人口腔鳞状细胞癌细胞系、两种间充质和两种上皮正常口腔细胞的细胞毒性。通过正常细胞与肿瘤细胞系的平均CC（50%细胞毒性浓度）之比评估肿瘤特异性（TS）。基于LowModeMD方法优化的构象计算物理化学、结构和量子化学参数。
在色满酮环7位有甲氧基且苯环4'位有羟基或甲氧基的3 - 亚苄基色满酮衍生物显示出相对较高的TS值，超过阿霉素（DXR）和5 - 氟尿嘧啶（5 - FU）。由于这些抗癌药物对正常角质形成细胞具有高度细胞毒性，因此对口腔癌和间充质正常细胞进行了QSAR分析。肿瘤特异性与3D - MoRSE描述符（与三维形状有关）和边缘邻接指数（与二维形状和极化有关）密切相关。在苯环3'位引入羟基显著提高了肿瘤特异性。
分子形状、大小和极化是评估3 - 亚苄基色满酮衍生物肿瘤特异性的有用指标。
